Cyclic dinucleotides have recently been described as potent cytosolic adjuvants of the immune system. They induce an antiviral innate immune response such as against HIV (Human Immunodeficiency Virus) and HSV (Herpes simplex virus), and also against cancer (WO2005/087238; WO2007/054279; WO2013/185052). Cyclic dinucleotides were previously identified in bacteria and known to be immunostimulatory.
This field has recently gained a lot of attention following the identification that a cyclic dinucleotide, cGAMP (2′-3′-cyclic GMP-AMP), also exists in vertebrates and can be endogenously synthetized by the enzyme cGAS upon recognition of cytosolic DNA.
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that signals by catalyzing the synthesis of a second messenger, cGAMP. cGAS binds double-stranded DNA in a sequence non-specific manner and this induces a conformational change in its enzymatic site allowing for cyclic GMP-AMP (cGAMP) synthesis ((Wu et al., 2012, Science, 339, 826-830; Sun et al., 2012, Science, 339, 786-791; WO2014/099824; Ablasser et al., 2013, Nature, 498, 380-384). Metazoan cGAMP bears both a canonical 3′-5′ and an unusual 2′-5′ phosphodiester bond. cGAMP binds and activates stimulator of interferon genes (STING). STING plays a central role in cytosolic DNA sensing by relaying a signal from upstream DNA sensors to activate transcription factors such as IRF3, which in turn drive IFN gene transcription. Interferons (IFN) play pivotal roles in the immune response to virus infection. IFN expression is induced by signaling pathways activated by sensors of virus presence, including cytosolic DNA sensors.
However, cyclic dinucleotides do not efficiently cross the plasma membranes of cells and have a limited potency when used without vectors. Current vectors mainly consist of lipid-based complexes such as lipofectamine, which have limited use in vivo due to their toxicity.
Therefore, there is a strong need for a vectorization means of cyclic dinucleotides, especially the promising cGAMP.